Bovine Leukemia Virus Small Noncoding RNAs Are Functional Elements That Regulate Replication and Contribute to Oncogenesis In Vivo

PLoS Pathog. 2016 Apr 28;12(4):e1005588. doi: 10.1371/journal.ppat.1005588. eCollection 2016 Apr.

Abstract

Retroviruses are not expected to encode miRNAs because of the potential problem of self-cleavage of their genomic RNAs. This assumption has recently been challenged by experiments showing that bovine leukemia virus (BLV) encodes miRNAs from intragenomic Pol III promoters. The BLV miRNAs are abundantly expressed in B-cell tumors in the absence of significant levels of genomic and subgenomic viral RNAs. Using deep RNA sequencing and functional reporter assays, we show that miRNAs mediate the expression of genes involved in cell signaling, cancer and immunity. We further demonstrate that BLV miRNAs are essential to induce B-cell tumors in an experimental model and to promote efficient viral replication in the natural host.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics*
  • Cattle
  • Cell Transformation, Neoplastic / genetics
  • Enzootic Bovine Leukosis
  • Gene Expression Profiling
  • Gene Expression Regulation, Viral / genetics*
  • High-Throughput Nucleotide Sequencing
  • Leukemia Virus, Bovine / genetics*
  • MicroRNAs / genetics*
  • Polymerase Chain Reaction
  • RNA, Viral / genetics
  • Sheep
  • Virus Replication / genetics*

Substances

  • MicroRNAs
  • RNA, Viral

Grants and funding

This work received financial support of the “Fonds National de la Recherche Scientifique” (FNRS), the Télévie, the Interuniversity Attraction Poles (IAP) Program “Virus-host interplay at the early phases of infection” BELVIR initiated by the Belgian Science Policy Office, the Belgian Foundation against Cancer (FBC), the “Centre anticancéreux près ULg” (CAC) and the "Fonds Léon Fredericq" (FLF), the “AgricultureIsLife” project of Gembloux Agrobiotech (GxABT), the “ULg Fonds Spéciaux pour la Recherche” and the “Plan Cancer” of the “Service Public Fédéral” and the Polish National Science Centre (decision 2012/07B/NZ6/03536). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.